The Role of Immunotherapy in Colon Cancer Treatment Discussed at ASCO 2018

For metastatic colorectal cancer resistant to standard treatments and carrying the genetic alteration called deficient mismatch repair (dMMR), the approval of drugs containing pembrolizumab and nivolumab brought immunotherapy into gastrointestinal oncology.

DNA is copied by placing a matching nucleotide opposite each nucleotide (for example, thymine (T) opposite adenine (A), and guanine (G) opposite cytosine (C)). When DNA is copied, involving the pairing of 3 billion nucleotides, some errors (such as mismatches) may occur. Normally, DNA repair systems detect and repair these errors. In some cancers, however, mismatches cannot be repaired; this condition is called deficient mismatch repair (dMMR) . Microsatellites are these unmatched DNA sequences that repeat and accumulate, producing a tumor mutation burden that causes mutations. These tumors are also called microsatellite instability-high (MSI-H).

Disease outcomes are more favorable in tumors with deficient mismatch repair (dMMR) than in those without it. Approximately 15% of all colon and rectal cancers have dMMR tumors, but the dMMR rate declines as stage increases (in stage 4 colorectal cancers, it falls to 4%).

Because dMMR status predicts differences in clinical course and response to immunotherapies, new treatment guidelines now recommend testing all patients with colon and rectal cancer.

dMMR testing can be performed by immunohistochemical staining, polymerase chain reaction (PCR), or next-generation sequencing (NGS). All 3 tests have sensitivity and specificity above 90%.

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dMMR-positive colon cancer has long been known to have a distinctive immune tumor microenvironment (tumor-infiltrating lymphocytes and a Crohn-like lymphoid reaction). Immune activity against these tumors led to the first trials of immune checkpoint inhibitors, and in May 2017 the FDA for colorectal cancer patients whose disease progressed after chemotherapy and who had exhausted other treatment options approved pembrolizumab (Keytruda).

Shortly afterward, in July 2017, the FDA, again for previously treated dMMR-positive colorectal cancers, approved nivolumab (Opdivo). This approval was based on results from CheckMate-142, in which 74 patients with dMMR-positive colorectal cancer were treated with single-agent nivolumab: the response rate was 31%, and 69% of patients had disease control for 12 weeks or longer.

The same study examined nivolumab combined with ipilimumab (Yervoy), an immunotherapy of another class, in 119 patients with dMMR-positive colorectal cancer. The combination was highly effective, with an overall response rate of 55%, 71% achieving 12-month progression-free survival (disease control with treatment), and 85% achieving 12-month overall survival.

Currently, standard second-line (and later) immunotherapies for colorectal cancers with dMMR tumors are nivolumab or pembrolizumab. However, we need to understand immunotherapy resistance mechanisms better, because not all patients with dMMR respond to these immunotherapy approaches.

Developments in Treating Colorectal Cancers Without dMMR

Immune checkpoint inhibitors alone do not appear effective in colorectal cancers without dMMR. Various approaches are being tested in clinical trials to overcome this problem, for example:

• Combining pembrolizumab with next-generation agents (such as the porcupine inhibitor CGX1321).
• Testing a combination of talimogene laherparepvec, a cancer vaccine approved for malignant melanoma skin cancer, and atezolizumab in triple-negative breast cancer and colorectal cancer metastatic to the liver.
• Immunotherapy drugs such as pembrolizumab and nivolumab act through T cells. A newer approach is to prevent natural killer (NK) immune cells from becoming inactive against cancer. Monalizumab, developed for this purpose, is being tested with another immunotherapy drug, durvalumab, in an initial human clinical trial for patients with colorectal cancer without dMMR. Early results show that among 37 patients, 3 responded to treatment—a group not normally expected to respond to immunotherapies.

In conclusion, standard second-line [and later] immunotherapies for colorectal cancers with dMMR tumors are currently nivolumab or pembrolizumab. However, we need to understand immunotherapy resistance mechanisms better, because not all patients with dMMR respond to these immunotherapy approaches.

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